Lck, short for lymphocyte-specific protein tyrosine kinase, is a Src-related non-receptor kinase. It is essential for T-cell development and activation, phosphorylating TCR-associated CD3 chains and downstream molecules in the T-cell antigen receptor (TCR) signaling pathway [1,2,3]. Lck also has roles in cell cycle control, adhesion, motility, proliferation, and differentiation [4].

Studies using Lck knock-out mice have shown that Lck is crucial for the initiation of TCR signaling, T-cell development, and T-cell homeostasis [2]. In mice with mutated LCK unable to bind co-receptors, there was a narrowed TCR repertoire for influenza A virus-derived pMHC-specific CD8 and CD4 T cells, and redirection of CD4-fated T cells to the CD8 lineage, indicating that LCK-co-receptor association is critical for T-cell lineage fidelity and maximizing antigen-specific T-cell repertoire diversity [5]. Also, complete LCK deficiency in a patient led to profound T-cell immune deficiency, reduced CD4 and CD8 surface expression, and a characteristic TCR signaling disorder [1].

In conclusion, Lck is a key regulator in T-cell-related biological processes. Research using Lck KO mouse models has revealed its importance in maintaining T-cell functions and lineage determination. Understanding Lck is crucial for further insights into T-cell-mediated immune responses and could potentially lead to new therapeutic strategies for T-cell-associated diseases such as T-cell acute lymphoblastic leukemia [6] and T-cell immune deficiencies [1].

References:

1. Lanz, Anna-Lisa, Erdem, Serife, Ozcan, Alper, Eken, Ahmet, Hauck, Fabian. 2023. A Novel Biallelic LCK Variant Resulting in Profound T-Cell Immune Deficiency and Review of the Literature. In Journal of clinical immunology, 44, 1. doi:10.1007/s10875-023-01602-8. https://pubmed.ncbi.nlm.nih.gov/38100037/

2. Bommhardt, Ursula, Schraven, Burkhart, Simeoni, Luca. 2019. Beyond TCR Signaling: Emerging Functions of Lck in Cancer and Immunotherapy. In International journal of molecular sciences, 20, . doi:10.3390/ijms20143500. https://pubmed.ncbi.nlm.nih.gov/31315298/

3. Isakov, N, Biesinger, B. . Lck protein tyrosine kinase is a key regulator of T-cell activation and a target for signal intervention by Herpesvirus saimiri and other viral gene products. In European journal of biochemistry, 267, 3413-21. doi:. https://pubmed.ncbi.nlm.nih.gov/10848956/

4. Kumar Singh, Pankaj, Kashyap, Aanchal, Silakari, Om. 2018. Exploration of the therapeutic aspects of Lck: A kinase target in inflammatory mediated pathological conditions. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 108, 1565-1571. doi:10.1016/j.biopha.2018.10.002. https://pubmed.ncbi.nlm.nih.gov/30372858/

5. Zhang, Justin B, Chaurasia, Priyanka, Nguyen, Angela, Zareie, Pirooz, La Gruta, Nicole L. 2025. LCK-co-receptor association ensures T cell lineage fidelity and maximizes epitope-specific TCR diversity. In Science immunology, 10, eadp5016. doi:10.1126/sciimmunol.adp5016. https://pubmed.ncbi.nlm.nih.gov/39982976/

6. Jarusiewicz, Jamie A, Yoshimura, Satoshi, Actis, Marisa, Yang, Jun J, Rankovic, Zoran. 2024. Development of an Orally Bioavailable LCK PROTAC Degrader as a Potential Therapeutic Approach to T-Cell Acute Lymphoblastic Leukemia. In Journal of medicinal chemistry, 67, 11868-11884. doi:10.1021/acs.jmedchem.4c00481. https://pubmed.ncbi.nlm.nih.gov/38973320/